Targeting the high-risk groups that are responsible for most of the transmission of HIV is a major challenge in biomedical research on HIV/AIDS. Substance abusers are one of the key high-risk groups, and, specifically, inner city crack cocaine users are three times more likely than non-users to be infected with HIV. We hypothesize that a vaccine that raises protective antibodies simultaneously to both cocaine and HIV could be a high-impact intervention in these populations. Such a vaccine may be feasible, because the first epitopes shown to protect against the acquisition of HIV have been identified by a consortium of scientists analyzing the results of the recent RV144 trial (Haynes et. al. NEJM 2012). Their analysis showed that the protective epitopes are located in the second variable loop (V2 loop) of the surface envelope glycoprotein of the HIV virus. Over the past few years, my laboratory has developed a technology platform for eliciting specific antibody responses from variable loop epitopes, including the V2 loop. Based on these data, we believe that we can develop an immunogen capable of eliciting HIV-protective antibodies. By coincidence, the same scaffold protein used to elicit these antibodies in our work has been used successfully as a cocaine vaccine in a clinical trial. Thus, an advanced starting point is present to develop a combined cocaine and HIV vaccine. Such a vaccine would be a precedent-setting molecular intervention at the intersection of HIV/AIDS and substance abuse, and may have a transformative effect on both fields. In the adaptation of our HIV vaccine immunogen design work to the problem of drug abuse, this proposed project represents a significant departure from the ideas and approaches that are currently being pursued in the our lab, so this proposal is ideal for the NIDA Avante-Garde Award Program for HIV/AIDS Research.